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Home , Enchondromatosis, Exostosis, Metachondromatosis, Noonan syndrome, Osteochondroma, Osteochondromatosis

CASE REPORT

Chondrosarcoma in : A Rare Case Report

Khodamorad Jamshidi, Tina Shooshtarizadeh, and Mehrdad Bahrabadi

Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran

Received: 23 Aug. 2016; Accepted: 08 Mar. 2017

Abstract- Metachondromatosis which was first described in 1971 by Maroteaux is a rare genetic disease consisting of and , caused by loss of function of the PTPN11 gene. It is distinct from other cartilaginous tumors such as multiple osteochondromas and hereditary multiple by the distribution and orientation of lesions, and pattern of inheritance. In Metachondromatosis osteochondromas typically occur in hands, feet, femur, and tibia while enchondromas commonly affect the pelvic and femurs. Both tumors are generally reported to regress in adulthood. To the best of our knowledge only one case of has been reported, and our case is the second reported case of Chondrosarcoma in metachondromatosis. © 2017 Tehran University of Medical Sciences. All rights reserved. Acta Med Iran 2017;55(12):793-799.

Keywords: Metachondromatosis; Enchondromas; Osteochondromas

Introduction calcifications in periarticular areas are often present (10) and appear similar to those observed Metachondromatosis, (MC), is a rare genetic disease in Trevor’s disease, which is also known as dysplasia characterized by the formation of enchondromas and epiphysealis hemimelica. The periarticular calcifications osteochondromas. There have been approximately 50 are due to peripheral enchondral ossification within cases reported in the literature since the first reported exophytic enchondromas (3). case in 1971 (2). It is distinct from hereditary multiple The enchondromas in MC in contrast of those of exostosis (HME), as the orientation of lesions in multiple enchondromas, most often affect the iliac crests metachondromatosis is towards rather than away from and the metaphyses of long bones with the similar the , and exostosis is commonly seen in the radiographic picture. These enchondromas may appear hands and feet (4). Loss of function of the protein as metaphyseal enchondromas, have a flowery tyrosine non- type 11 (PTPN11) appearance around joints (8,9,11), or be similar to lytic tumor suppressor gene has been reported as a cause of metastatic lesions (7,8). this disease (5). Metachondromatosis is inherited as an The natural history of metachondromatosis is autosomal dominant disease with incomplete penetrance reported as one of spontaneous regression during (5) and is different from other , such childhood (10), although some lesions may remain into as Ollier’s disease and , which are adulthood. Like other enchondromatoses and multiple sporadic in nature (5,6). exostosis, new lesions do not appear after skeletal The metachondromatosis consists of multiple maturity (6). This condition is different from other exostosis which is true osteochondromas with enchondromatoses due to its lack of potential for cartilaginous caps and characteristically points toward malignant transformation; however, there is a case the adjacent joint rather than away from it. This report regarding a grade 2 Chondrosarcoma arising in an exostosis, which often involve the bones of the hands in a patient with metachondromatosis (3). and feet, do not produce shortening or growth There are some reported complications of disturbance of the affected bone (7) however, case metachondromatosis which are attributable to pressure reports have documented deformities in the distal part of effect of osteochondromas, or enchondromas. These tibia and fingers (8,9) and tibia (8). include common peroneal nerve palsy secondary to

Corresponding Author: M. Bahrabadi Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran Tel: +98 +98 21 33542022, Fax: +98 21 33542020 , E-mail address: [email protected]

Chondrosarcoma in metachondromatosis compression by exostosis near the fibular head, resulting long before he was visited by us. Our patient did not in numbness and footdrop (8) with later recovery after report any family member as having excision of the exostosis, of the metachondromatosis, enchondromas, or femoral head in patients with lesions around the femoral osteochondromas. neck (12,13) due to the disruption of lateral epiphyseal Physical examination showed a tender mass at the vessels (7), and skin necrosis overlying a large lesion anterolateral aspect of the proximal part of the left tibia. (8). The pathological fracture may also be present in He had also a hard mass on the lateral aspect of his right metachondromatosis (14). The aim of this study was to arm. report on a very rare case of chondrosarcoma which Anteroposterior and lateral plain radiographs of the happened in metachondromatosis, and to the best of our left knee showed a radiolucent lesion in proximal tibial knowledge is the second reported case in the English epiphysis and accompanied with a flocculent literature. calcification. Lateral cortex of the tibia was eroded and showed sunburst periosteal reaction at the level of the Case Report metaphysis (Figure 1a and b). All these features were consistent with an aggressive chondroid tumor. There A forty-two-year-old man was admitted to our were multiple enchondromas in metaphysis, and hospital complaining of left leg pain for two years. The of left femur, and left tibia (Figure 1c). pain had been worse and was accompanied by a mass Radiographies of his right humerus showed an two months before the admission. Pain and mass were of the shaft of the humerus, and an localized to the upper third of the leg. The pain had been osteochondroma of the right scapula (Figure1d). Other worse at night but was also present during the daytime. exostoses and enchondromas were also present in his The patient report having multiple bony protrusions right hand, and both feet (Figure 1e and f). (exostosis) in his hands and feet since the age of 11,

Figure 1. (a) and (b) Lytic lesion of the proximal part of the tibia, and erosion of the lateral cortex, Anteroposterior, and lateral views respectively;(c) Enchondromas in the metaphyses, and shafts of both femurs;(d) Osteochondroma of the shaft of the humerus, and right scapula (arrow), with soft tissue classification in axilla;(e) Exostoses (arrows) and enchondromas of the hands ; (f) Exostosis and enchondromas of both feet

794 Acta Medica Iranica, Vol. 55, No. 12 (2017) Kh. Jamshidi, et al.

T1 weighted magnetic resonance imaging revealed a aspect of the proximal tibia. On T1 weighted MRI, the low intense lobulated lesion involving the left proximal lesion was iso signal as compared to muscle (Figure 2a). tibial epiphysis, metaphysis, and upper part of the On T2 weighted MRI images, the tumor had bright diaphysis, with soft tissue component around the lateral signal (Figure 2b).

Figure 2. (a) Coronal T1-weighted magnetic resonance imaging of the left tibia shows a lesion involving epiphysis, metaphysis, and upper part of the diaphysis, with soft tissue component. The lesion has iso-intense signal as compared to muscle. (b) Axial T2-weighted magnetic resonance imaging with fat suppression of the left tibia illustrates a high signal intensity lesion in proximal tibia with a soft tissue component

A biopsy was planned for this patient and was knee joint line, and was accompanied with a soft tissue performed through an anterolateral incision to the component at its proximal extent (Figure 3a). proximal tibia. Histological examination showed a Histological examination of the resected proximal tibia moderately cellular to hyper cellular cartilaginous showed a cartilaginous consistent with an neoplasm with features suggestive of Chondrosarcoma intermediate-grade to high-grade (grade II/III) including cellular atypia (Figure 3). The reported Chondrosarcoma (Figure 3b and c). Surgical margins diagnosis by our hospital’s bone pathologist was were declared as free in the histopathology exam, and Chondrosarcoma grade II/III of the WHO classification. the nearest surgical margins were reported 1.5 Due to the presence of soft tissue component in this centimeters. Follow-up visits were scheduled every three tumor, and considering the histopathology report, we months for the first two years after surgery. In each decided to perform a wide excision. Through an follow-up, we performed a physical examination and anterolateral approach, wide excision of the proximal asked for plain radiographies of the chest, the operated tibia was performed, and MUTARS prosthesis was used leg, and any symptomatic areas of his skeleton. At two for reconstruction of the defect. Gross examination of years after the operation, this patient was alive, and there the specimen showed a nodular, translucent, whitish was no evidence of local recurrence or distant tissue which completely filled intramedullary space of metastases. The last radiography of the left knee was the tibial epiphysis, metaphysis, and proximal diaphysis consistent with a well-fixed prosthesis (Figure 4). down to a distance of about fifteen centimeters from the

Acta Medica Iranica, Vol. 55, No. 12 (2017) 795 Chondrosarcoma in metachondromatosis

Figure 3. (a) Sagittally bisected resection specimen of the proximal tibia showing a destructive nodular, whitish mass inside tibia with a soft tissue component outside of it (arrow) ;( b) photomicrograph of the tumor showing a myxoid cartilage neoplasm with diffuse proliferation of spindle and satellite cells with lobular pattern, (H and E 100X); (c) Photomicrograph of the tumor showing a cellular hyaline cartilage with mild nuclear atypia of . Vesicular nuclei with prominent nucleoli are seen (arrows), (H and E 400X)

Figure 4. Postoperative radiography of the patient showing MUTARS prosthesis in good condition

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Discussion metachondromatosis (2,16,17). Loss of function of the PTPN11 gene has been reported as a cause of Metachondromatosis is a rare which metachondromatosis in two studies (5,18), a fact that is described as a combination of osteochondromas and further distinguishes this disorder from multiple enchondromas in the hands, feet, long bones, iliac crests, exostosis and Ollier’s disease. There are other and spine (1). overlapping syndromes, including , Metachondromatosis is usually noticed during the LEOPARD syndrome, and Noonan-like disorder with first decade of life (15). Exostoses in multiple giant cell lesion syndrome, which are caused by metachondromatosis commonly occur in the digits, and gain of function of PTPN11(19,20). toes, and involve the metaphyses and epiphyses (15). Diagnosis is based on clinical signs, radiographic Exostoses may decrease in size and spontaneously findings, and familial history; if a molecular diagnosis is regress. Enchondromas in metachondromatosis are confirmed, then this can be used to aid diagnosis in other commonly found in the pelvis and the metaphyses of family members (15). There are some differences long bone (15). They may be similar to lesions seen in a between authors regarding the histopathology of lytic metastatic disease (7,8) and have a periarticular metachondromatosis. Several reports found typical flowery appearance (8,9,11). The reported locations of enchondromas and osteochondromas with cartilaginous enchondromas include the iliac crest, proximal and caps (7,8,13,21,22); however, there is a report regarding distal end of the femur, the proximal portion of the the presence fibrous caps overlying cartilaginous cores fibula, and humerus, the distal end of the tibia, and the (5). radius, and hands and feet (4,7,9,11) periarticular On the basis of histological parameters, calcifications were also reported in metachondromatosis Chondrosarcoma are divided into three grades. Grade I (3). Our patient had some enchondromas in the Chondrosarcoma is described as a cartilage neoplasm metaphysic, and diaphysis of both femurs, and one with the exclusive presence or marked preponderance of exostosis in the shaft of the right humerus, and right small, densely-straining nuclei. Multiple nuclei (two or scapula each, as well as many enchondromas elsewhere more) within one lacuna is commonly seen in grade I (Figure 1). He had also soft tissue calcifications in his tumors (23). Grade II Chondrosarcoma represents right axilla. Our patient did not recall any family histologically as areas in which a significant proportion member as having metachondromatosis, enchondromas, of the nuclei are at least of moderate size, but the mitotic or osteochondromas, but he reported having multiple rate is low (23). The principal criteria of bony protrusions (exostosis) in his hands and feet since Chondrosarcoma Grade III are the presence of two or the age of 11. The clinical course of more mitoses per 10 high power field in the most active metachondromatosis is unpredictable because there may area s of the tumor (23). Grade I Chondrosarcoma is be the simultaneous growth of some of the lesions and considered as low‐grade and grades II and III as high‐ regression of the others. It does not generally cause grade (24). The therapeutic options for different grades bowing of the long bones, joint deformity or joint of Chondrosarcoma are thorough curettage, in the case subluxation (7). Nerve paralysis or vascular of grade I tumors, or complete resection, for grade II and complications may occur, and unilateral or bilateral III cases (25). Legg-Calvé-Perthes-like changes in the femoral head, Primary Chondrosarcoma arises de novo, whereas resembling osteonecrosis has been reported (7,8,11). secondary Chondrosarcoma develops in association with The includes multiple a predisposing condition such as an enchondroma or osteochondromas, (MO), and multiple osteochondroma (26,27). Malignant transformation of an enchondromatosis (Ollier’s disease). The fact that the osteochondroma or an enchondroma to Chondrosarcoma lesions are oriented towards rather than away from is rare. The risk of Chondrosarcoma is greater in patients epiphyses helps distinguish metachondromatosis from with multiple enchondromas, such as Ollier’s disease multiple exostosis. Enchondromas in Ollier’s disease are and Maffucci syndrome, and in those with hereditary almost always unilateral, and this disease is not a multiple exostosis. In Ollier’s disease, this risk was first hereditary condition like metachondromatosis. The estimated to be around fifty percent while new reports prevalence of multiple osteochondromas is estimated to suggest a lower risk around twenty-five to thirty percent be 2/100,000(16) and Ollier’s disease 1/100,000 (17), (28,29). The risk of malignant transformation in and both are significantly more prevalent than Maffucci syndrome is even higher with estimates around

Acta Medica Iranica, Vol. 55, No. 12 (2017) 797 Chondrosarcoma in metachondromatosis one hundred percent (29). In hereditary multiple mutations in PTPN11 cause metachondromatosis, but not exostosis the risk of malignant change is lower than the or Maffucci syndrome. PLoS Genet risk in multiple enchondromas and is reported to be 2011;7:e1002050. around five to twenty-five percent (30). The risk of 6. Bovée JV. Multiple osteochondromas. Orphanet J Rare malignant degeneration with other cartilaginous Dis 2008;3:3. disorders such as metachondromatosis is not totally 7. Wenger DR, Birch J, Rathjen K, Tobin R, Billman G. unexpected. To the best of our knowledge, however, this Metachondromatosis and avascular necrosis of the is the second case of the malignant transformation of a femoral head: a radiographic and histologic correlation. J metachondromatosis-associated enchondroma to a Pediatr Orthop 1991;11:294-300. Chondrosarcoma. 8. Bassett G, Cowell H. Metachondromatosis. Report of four Treatment and surveillance recommendations in MC cases. J Bone Joint Surg Am 1985;67:811-4. are difficult to make in the absence of a larger number of 9. Hunter A, Kozlowski K, Hochberger O. reported cases in the literature. In asymptomatic and Metachondromatosis. Can Assoc Radiol J 1995;46:202-8. uncomplicated cases, no treatment is warranted. For 10. Giedion A, Kesztler R, Muggiasca F. The widened functional limitation or deformity of the fingers and toes spectrum of multiple cartilaginous exostosis (MCE). which are severe, surgical intervention can be Pediatr Radiol 1975;3:93-100. considered for removing of the exostoses. Other 11. BEALS RK. Metachondromatosis. Can Assoc Radiol J Indications for surgical intervention are predominantly 1982;169:167-70. symptomatic and are related to pain and nerve 12. Keret D, Bassett GS. Avascular necrosis of the capital compression. Malignant transformation has only been femoral epiphysis in metachondromatosis. J Pediatr observed in one case but should be considered as an Orthop 1990;10:658-61. indication for intervention. Based on observations of the 13. Herman T, Chines A, McAlister W, Gottesman G, Eddy natural history of other conditions causing the formation M, Whyte M. Metachondromatosis: report of a family of enchondromas and osteochondromas, regular bi- with facial features mildly resembling annual clinical examination, skeletal survey of regions trichorhinophalangeal syndrome. Pediatr Radiol with lesions difficult to examine clinically (chest, pelvis, 1997;27:436-41. scapula) and repeat imaging of lesions that enlarge or 14. Banks RJ. P Pathological fractures; a consideration with become painful appears appropriate, with a view to metachondromatosis and differential diagnoses. minimize unnecessary irradiation (6). and Gauchers disease. Australas Although many reports shows that the regression of Chiropr Osteopathy 2002;10:105-10. lesions appears to be the usual fate (2), Some 15. Mcfarlane J, Knight T, Sinha A, Cole T, Kiely N, complications are important to notice in Freeman R. Exostoses, enchondromatosis and metachondromatosis. These include femoral head metachondromatosis; diagnosis and management. Acta avascular necrosis, peroneal nerve palsy and most Orthopaedica Belgica 2016;82:102-5. importantly, malignant transformation. 16. Schmale GA, Conrad Er, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint References Surg Am 1994;76:986-92. 17. Silve C, Jüppner H. Ollier disease. Orphanet J Rare Dis 1. Maroteaux P. La metachondromatose. Z Kinderheilk 2006;1:1. 1971;109:246-61. 18. Sobreira NL, Cirulli ET, Avramopoulos D, Wohler E, 2. Fisher TJ, Williams N, Morris L, Cundy PJ. Oswald GL, Stevens EL, et al. Whole-genome sequencing Metachondromatosis: more than just multiple of a single proband together with linkage analysis osteochondromas. J Child Orthop 2013;7:455-64. identifies a Mendelian disease gene. PLoS Genet 3. Mavrogenis AF, Skarpidi E, Papakonstantinou O, 2010;6:e1000991. Papagelopoulos PJ. Chondrosarcoma in 19. Jorge AA, Malaquias AC, Arnhold IJ, Mendonca BB. Metachondromatosis. J Bone Joint Surg Am Noonan syndrome and related disorders: a review of 2010;92:1507-13. clinical features and mutations in genes of the 4. Kennedy L. Metachondromatosis. Radiology RAS/MAPK pathway. Horm Res Paediatr 2009;71:185- 1983;148:117-8. 93. 5. Bowen ME, Boyden ED, Holm IA, Campos-Xavier B, 20. Tartaglia M, Gelb BD. Noonan syndrome and related Bonafé L, Superti-Furga A, et al. Loss-of-function disorders: genetics and pathogenesis. Annu Rev

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